The Lung Cancer Biology Section has undertaken a study of the role atrial natriuretic peptide, renin, angiotensin, and aldosterone play in sodium homeostasis in a prospective trial of patients with lung cancer. Fifty patients, 31 with small cell lung cancer and 19 with non-small cell lung cancer participated in this clinical trial. Eleven patients presented with hyponatremia; 10 patients with small cell lung cancer (32%) and 1 patient with non-small cell lung cancer. All 11 patients who presented with hyponatremia had inappropriately elevated levels of AVP. Elevated plasma AVP levels were highly correlated with the presence of hyponatremia (p < 0.00001). Initial plasma atrial natriuretic peptide levels were not associated with hyponatremia (p = 0.73). A 500 ml saline infusion caused a physiological decrease in aldosterone levels (p < 0.05) followed by an increase after the infusion was completed (p < 0.05) but the other hormones did not appear to be abnormal or under physiological change. A successor study has been initiated where patients are placed on a 4 day sodium and fluid restricted diet. Their serum and urine electrolytes, plasma ANP, AVP, and aldosterone are measured daily. Patients are then restudied at the time of best response and relapse. Tumors and tumor cell lines from small cell lung cancer (SCLC) patients with and without hyponatremia have been studied to determine if ectopic production and prohormone processing of atrial natriuretic peptide (ANP) may play a role in hyponatremia of malignancy. RNase protection assays showed a 200 base pair protected fragment in the mRNA isolated from the tumor and tumor cell line from a patient with hyponatremia. HPLC characterization of the cellular extract and conditioned medium from the tumor and tumor cell line from patient number 6 demonstrated ANP immunoreactivity in the same fraction as ANP-(S-99-Y126). The tumor cell line contains a 60 kD mol wt protein with enzyme activity that hydrolyzes synthetic pro-ANP substrates and catalyzes the formation of ANP-(S99-Y126). We have shown a tumor cell line from a patient with hyponatremia is able to ectopically produce, process and secrete ANP in the same immunoreactive form as the biologically active molecule. NCI-H1284 contains an enzyme which can cleave precursors at the same amino acid sequences as needed to produce ANP-(S99-Y126) from pro-ANP.